P735: THE ROLE OF SF3B1 MUTATIONS IN MYELODYSPLASTIC SYNDROMES
Authors: S. Huber, S. Hutter, M. Meggendorfer, G. Hoermann, W. Walter, C. Baer, W. Kern, T. Haferlach, C. Haferlach
Journal: HemaSphere (2022)

Background:SF3B1 is one of the most commonly mutated genes in patients with myelodyplastic syndromes (MDS), associated with ring sideroblasts (RS) and an indolent disease course. Malcovati et al. proposed MDS with mutated SF3B1 fulfilling certain criteria as distinct MDS entity (Malcovati et al., Blood, 2020). Aims: Study the SF3B1 mutation in MDS with respect to the genomic landscape, AML transformation rate and clinical outcome. Methods: We analyzed 734 patients diagnosed with MDS based on cytomorphology, cytogenetics and molecular genetics and classified according to WHO classification 2017. Amplification-free WGS was performed with a median coverage of 103x (Illumina, San Diego, CA). Reads were aligned to the human reference genome (GRCh37, Ensembl annotation, Isaac aligner) and variants were called using Strelka Somatic Variant Caller v2.4.7. Results:SF3B1 mutations were identified in 231 of 734 (31%) MDS patients and were mainly found in MDS-RS (171/200; 86%; MDS-RS-SLD: 43/51, 84%; MDS-RS-MLD: 128/149; 86%). In addition, 13% (37/300) of MDS with excess blasts (MDS-EB1/2) and 20% of MDS with isolated del(5q) harbored SF3B1 mutations. In the total cohort SF3B1 mutations were associated with better outcome (median OS: 79 vs. 53 month; p<0.0001). Within the different MDS entities SF3B1 mutations were favorable in MDS-RS-SLD (median OS: 106 vs. 25 month; p=0.009), MDS-RS-MLD (median OS: 82 vs. 64 month; p=0.049) and MDS-EB-2 (median OS: 129 vs. 25 month; p=0.011), but were associated with shorter survival in MDS with isolated del(5q) (median OS: 69 vs. 79 month; p=0.044). 144/231 (62%) SF3B1 mutated samples fulfilled the criteria proposed by Malcovati et al. (SF3B1ent). These cases were associated with longer survival compared to SF3B1 mutated samples not falling into the proposed SF3B1 entity (SF3B1nent). Within SF3B1ent 47% (67/144) did not harbor any additional mutation resulting in an average of 1.8 mutations (including SF3B1) in this group. SF3B1nent patients showed on average more mutations (MDS with isolated del(5q): 1.9; MDS-EB: 2.7; MDS-RS: 3.1). The most frequent additional mutations in all SF3B1 mutated patients were TET2 (29%), DNMT3A (16%) and ASXL1 (9%). Regarding cytogenetic abnormalities, 69/231 (30%) SF3B1 mutated samples showed aberrant karyotypes (SF3B1ent: 27/144, 19%; SF3B1nent: 42/87, 48%). Of SF3B1 mutated patients 7% (15/231) progressed to AML compared to 15% (75/503) of SF3B1 wildtype patients (median follow-up: 112 months). Notably, 80% of SF3B1nent showed AML transformations in comparison to 20% of SF3B1ent (median follow-up: 122 and 112 months). Within the 15 SF3B1 mutated patients progressing to AML 47% showed additional RUNX1 and 27% DNMT3A or TET2 mutations at MDS diagnosis. In AML-transforming patients with a low SF3B1 variant allelic frequency (VAF, n=2) additional spliceosome mutations (SRSF2 or ZRSF2) were identified at the time of diagnosis. Two other SF3B1 mutated patients showing disease progression to AML harbored MECOM rearrangements when MDS was diagnosed. During progression one patient gained a MECOM rearrangement and two patients other chromosomal aberrations present in the AML state. Image:Summary/Conclusion:SF3B1 mutations occur in several MDS entities, are associated with good clinical outcome and mainly co-occurred with TET2 mutations. Patients showed a better prognosis (longer OS, lower AML transformation rate) when categorized into the proposed SF3B1 entity. AML transformation of SF3B1 mutated MDS patients is determined by the entire genomic landscape indicating RUNX1 as potential driver.